Segmental corymbiform congenital melanocytic naevi: Implications for melanocytic embryology

Abstract

Congenital melanocytic naevi (CMN) are common birthmarks that present a broad phenotypic spectrum, ranging from small single to extensive multiple CMN. Cohort genotyping studies have demonstrated that CMN arise from mosaic missense pathogenic variants in NRAS (67%) or BRAF (5%), mosaic BRAF fusions (7%)^1-4 or in a single case MAP2K1.⁵

Two recurrent patterns of large congenital melanocytic lesions have been defined.⁶ The outline of the segmental pattern has strict midline cut-offs and straight parallel edges, whereas that of the non-segmental pattern is unaffected by the midline, forms circular/ovoid shapes⁶ and is the commoner pattern for CMN. As these two patterns are consistent across genetically different somatic clonal diseases and are mutually exclusive, it has been hypothesised that they represent the embryological fields of two different cells of origin.⁶ To interrogate this hypothesis further, and in particular to exclude that the two patterns are generated simply by different genetic variants affecting the same embryological cell, we assemble here a rare series of CMN clustered in the segmental pattern. Seven patients were studied with written informed consent as per local Research Ethics Committee approvals where required. DNA was extracted by standard methods from affected skin biopsies and underwent deep targeted sequencing to a mean depth of 1500–2500× using Illumina technology (panel R327 Mosaic disorders, UK national genomic test directory). Demographic, phenotypic, genotypic and histological findings are summarized in Table 1 and illustrated in Figure 1a–g. All patients had normal neurodevelopment and screening MRI of the CNS was normal in the two in whom it was performed. Genetic testing was not performed in patient 4 as per the family and patient's wishes.

This series delineates this rare phenotypic variant of CMN as ‘segmental CMN’. Key features are an outline segmental pigmentary pattern, within which are multiple similar sized individual naevi in clusters for which we suggest the term corymbiform. Derived from the botanical term ‘corymb,’ it refers to an inflorescence where multiple flower heads are borne on different length pedicles (Figure 1h), bringing them to a common level. Genotyping of tissue from the segmental CMN demonstrates a very similar genotypic profile to the classical non-segmental pattern. As such, these data support a different melanocyte precursor population rather than a different genotype as the cause of the two patterns.

We would classify these lesions as single CMN, as despite the clusters of naevi they all occupy parts of what we recognise to be a single segmental “field” from other mosaic disorders affecting pigmentation such as mosaic NF1-neurofibromatosis type 1, and mosaic GNAS-McCune Albright syndrome.⁶ The lack of a background diffuse increase in pigmentation in that field in these segmental CMN patients is notable, and potentially important embryologically. We would very tentatively suggest that the corymbiform grouping of lesions within the segmental outline pattern could be the result of the genetic variant arising in the Ademeyko-Ernfors melanocyte,⁷ a cell with melanocytic differentiation potential which differentiates from a Schwann cell precursor, which in turn arises from the neural crest (Figure 1h). Migration of clonally variant cells into the skin along neural fibres could produce this type of clustering of naevi. The lack of diffuse background might suggest that the corresponding classical dorsolateral neural crest melanocyte has not been affected by the variant.

In conclusion, the delineation of the phenotype/genotype of segmental corymbiform CMN informs the debate on the embryonic origins of melanocytes and contributes to the understanding of the effects of different NRAS variants in melanocytic precursors. Future phylogenetic lineage tracing of lesions from the two patterns should help identify the cells of origin.

VK and NK were funded by the UK National Institute for Health and Care Research (grant NIHR300774). This work was supported by the UK NIHR through the Biomedical Research Centre at Great Ormond St Hospital for Children NHS Foundation Trust and UCL GOS Institute of Child Health.

The authors have declared that no conflict of interest exists.

The study was approved as per the local Research Ethics Committee approvals where required.

Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors stating that the patients' parents/guardians in this manuscript gave consent with the understanding that this information may be publicly available.